The metallothioneins (MTs) are a group of small (61 amino acids), cysteine rich proteins that bind heavy metals such as cadmium, zinc, mercury, lead, and copper and are thought to play a role in metal detoxification or in the metabolism and homeostasis of metals. MTS are present in a wide variety of eucaryotes including invertebrates, vertebrates, plants, and fungi. The primary structure of the vertebrate MTs is strongly conserved between species, particularly the positions of the cysteine residues which serve to chelate heavy metal ions via thiolate complexes.
At least two closely related but chromatographically distinct isoforms of MT, MT-I and MT-II, have been observed in every vertebrate species examined. All isoforms of MT sequenced thus far share 20 cysteine residues found in the same positions and lack aromatic amino acids or leucine (Schmidt, C. J. and Hamer, D. H. (1983) Gene 24:137-46; Schmidt, C. J. et al. (1985) J. Biol Chem. 260(12):7731-37). MT-II isoforms differ from MT-I only in the presence of an aspartate residue at position 10 or 11, while MT-I contains either glycine or valine at these positions. Recently, a third class of MTS, MT-0, has been discovered in human liver and is characterized by a negatively charged amino acid at position 8 (glutamate) and a lysine substitution at the highly conserved Glu.sub.23 (Sournillion, A. Et al. (1992) Eur. J. Biochem. 209:999-1004) In humans, only a single sequence of MT-0 and MT-II have been found, while at least six isoforms of MT-I have been identified. The various isoforms of MT-I differ only by a few residues distributed throughout the molecule. The localization and identification of 12 functional MT genes on human chromosome 16 indicates that several additional MT isoforms exist.
The reason for multiple human MT genes is unclear. It is possible that different isoforms are responsible for binding different metals, or that different control sequences for the transcription of these various isoforms respond to different stimuli, such as heavy metals, glucocorticoids, or enterotoxin ( Schmidt, et al. supra). A third possibility is that multiple isoforms could play different roles in metal homeostasis during development or in different tissues.
Acute or chronic exposure to heavy metals such as lead, arsenic, mercury or cadmium leads to a variety of diseases and disorders involving neuromuscular, CNS, cardiovascular, and gastrointestinal effects. MTs may play a role in the prevention or alleviation of these conditions. In addition, MTs are transcriptionally regulated by glucocorticoids, which suggests that MTs have a direct role in the effects of glucocorticoids to treat inflammatory disease, immune disorders, and cancer.
Discovery of new proteins related to metallothioneins, and the polynucleotides that encode them, satisfies a need in the art by providing new diagnostic or therapeutic compositions useful in diagnosing and treating heavy metal toxicity, cancer, inflammatory disease and immune disorders.